succinylcholine chloride (2 mg/kg) and the monkeys were ventilated with positive pressure 100% oxygen. Seizure expression was monitored via scalp electroencephalog-raphy (EEG), electromyogelectroencephalog-raphy, and visuomotor mani-festations in a nonparalyzed limb. One subject (No. 1) had a chronically implanted intracerebral multicontact electrode in place, permitting recording of intracerebral EEG and TMS-induced voltage.5
The 2 trials with the commercial device did not pro-duce a seizure. In contrast, each of the subsequent 8 trials with the custom device produced a generalized tonic-clonic seizure ranging in duration from 10 to 20 seconds, docu-mented by motor manifestations, electromyography, scalp EEG, and intracerebral EEG results. Intracerebral record-ings documented that peak induced voltage with the cus-tom TMS device matched that achieved with electrocon-vulsive shock and occurred in the prefrontal cortex. The commercially available device achieved less than half the voltage induced by electroconvulsive shock.6
Magnetic seizure threshold was titrated by adminis-tering trains of increasing duration until a generalized sei-zure was induced. Due to coil heating, no more than 2 trains could be administered in a single session. Thus, the vari-ous train durations were administered across 4 sessions. Sei-zures were reliably obtained with parameter settings of 40 Hz, 90% of maximal stimulator output, administered for 4 to 5 seconds. This represents stimulation at more than 400% of the electromyographically defined motor thresh-old. Stimulation at this intensity is far in excess of recom-mended safety guidelines for human use of subconvulsive rTMS.7The purpose of this experiment, however, was
in-tentional seizure induction, and high intensities were needed to overcome the anticonvulsant effects of anesthesia.
These findings demonstrate the feasibility of rTMS sei-zure induction under general anesthesia. The fact that the commercial device was incapable of eliciting seizures sug-gests that the broader pulse width and/or faster frequency of the custom device were needed. Future work will focus on parameterization and safety to support clinical use in hu-mans as a novel convulsive treatment. The enhanced con-trol over dosage and focality achieved with rTMS may of-fer the capacity to focus seizure induction in the prefron-tal cortex, thereby improving the efficacy and limiting the cognitive side effects due to medial temporal lobe stimu-lation. This animal model in which magnetic seizure thresh-old can be easily assessed, will provide information relevant to safety guidelines for the human use of nonconvulsive and convulsive rTMS, and may provide a new model for stud-ies of epilepsy.
Sarah H. Lisanby, MD Bruce Luber, PhD Harold A. Sackeim, PhD
Department of Biological Psychiatry New York State Psychiatric Institute 1051 Riverside Dr New York, NY 10032 A. D. Finck, MD New York Charles Schroeder, PhD Orangeburg, NY
This work was supported by grants from the National Al-liance for Research in Schizophrenia and Depression, Great Neck, NY (Drs Lisanby and Sackeim); grants MH35636 (Dr Sackeim), MH01577, and MH60884 (Dr Lisanby) from the National Institutes of Mental Health, Bethesda, Md; and The Magstim Company Ltd, Whitland, Wales (Drs Lisanby and Sackeim).
Presented at the Society of Biological Psychiatry an-nual meeting, Washington, DC, May 14, 1999.
Corresponding author: Sarah H. Lisanby, MD, De-partment of Biological Psychiatry, New York State Psychi-atric Institute, 1051 Riverside Dr, Box 126, New York, NY 10032-2695.
1. Sackeim HA, Prudic J, Devanand DP, Kiersky JE, Fitzsimons L, Moody BJ, McElhiney MC, Coleman EA, Settembrino JM. Effects of stimulus intensity and electrode placement on the efficacy and cognitive effects of electrocon-vulsive therapy. N Engl J Med. 1993;328:839-846.
2. Wassermann EM, Cohen LG, Flitman SS, Chen R, Hallett M. Seizures in healthy people with repeated “safe” trains of transcranial magnetic stimuli. Lancet. 1996;347:825-826.
3. Ziemann U, Steinhoff BJ, Tergau F, Paulus W. Transcranial magnetic stimu-lation: its current role in epilepsy research. Epilepsy Res. 1998;30:11-30. 4. Weissman JD, Epstein CM, Davey KR. Magnetic brain stimulation and brain
size: relevance to animal studies. Electroenceph Clin Neurophysiol. 1992;85: 215-219.
5. Lisanby SH, Luber BL, Schroeder C, Osman M, Finck D, Amassian V, Arezzo J, Sackeim HA. rTMS in primates: intracerebral measurement of rTMS and ECS induced voltage in vivo. Electroenceph Clin Neurophyiol. 1998;107:79P. 6. Lisanby SH, Luber BM, Finck D, Osman M, Schroeder C, Sackeim HA. Mag-netic stimulation therapy: a novel convulsive technique. Biological Psychia-try. 1999;45:64-65S.
7. Wassermann EM. Risk and safety of repetitive transcranial magnetic stimu-lation: report and suggested guidelines from the International Workshop in the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Electroencephalogr Clin Neurophysiol. 1998;108:1-16.
The Mood-Lowering Effect of Tryptophan Depletion: Possible Explanation
for Discrepant Findings
T
ryptophan depletion (TD) is an experimental pro-cedure for studying brain serotonin function. The mood-lowering effect of TD has been demon-strated in formerly depressed patients treated with selec-tive serotonin reuptake inhibitors (SSRIs) or monoamine oxidase inhibitors1and in medication-free women with ahistory of recurrent depressive episodes.2Typically, a little
more than half of the patients experience the effect. It is not exactly clear why some patients experience the effect while others do not. Several studies have recently found that the effect may be less consistent than previously thought. Moore et al3observed no effect on mood in fully
remitted patients medicated with SSRIs. In a study4of
pa-tients who had responded to treatment with citalopram, only 5 of 12 patients relapsed, and the effect seemed to be clinically significant in only 1 patient. In a third study,5
only 33% of 21 patients experienced a relapse. Moore et al3suggest that their unexpected finding may be related
to sample differences. In comparison with earlier studies, their patients had been in treatment longer and were less depressed. Therefore, the effect of TD may be limited to recently recovered, medicated patients.3However,
clini-cally significant symptom increases have been observed in euthymic patients who had not been receiving medi-cations for at least 6months.2Another factor that might
be involved is a patient’s history of suicidal ideation.6 (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 58, FEB 2001 WWW.ARCHGENPSYCHIATRY.COM
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A simple explanation for the negative findings may be insufficient depletion. In Moore et al,3the mean
re-duction of free plasma tryptophan levels was 52%. This is lower than the typically reported 75% to 90% mean reduction. However, because this value was signifi-cantly different from the reduction in the placebo con-dition (5.6%), the authors consider their study success-ful in obtaining a contrast between TD and placebo conditions. However, the extent of depletion needed to achieve reliable mood effects has never been estab-lished. It cannot be ruled out, therefore, that there is a threshold that needs to be exceeded before an effect on mood occurs. Some indirect evidence supports this hy-pothesis. For instance, in the citalopram-responders study,4total plasma tryptophan reduction was also
mod-est: 44.6% (free levels not reported). Furthermore, Del-gado et al1found a significant negative correlation
(r=−0.60) between minimum level of free tryptophan and depression score. Inspection of their Figure 41(p 415)
sug-gests that a nonlinear relationship is also possible. Ten of 12 patients with free tryptophan levels lower than or equal to 1 μmol/L had a relapse, compared with only 2 of 9 patients with a level greater than 1 μmol/L. In the study by Bremner et al,5tryptophan reductions were not
statistically different between patients who relapsed and those who did not. However, with the threshold hypoth-esis in mind, the difference may be clinically significant. The reduction in free plasma tryptophan in the relapse group was 77.9%, compared with 57.5% in the no-relapse group. Finally, a recent study found that a 67% reduction of free tryptophan produced the expected wors-ening of depressive symptoms, whereas a 34% reduc-tion did not.7These studies5suggest that the
hypoth-esized threshold lies somewhere around a 60% reduction of free plasma tryptophan.7However, it may be that the
hypothesized threshold should be defined in terms of the ratio between tryptophan level and large neutral amino acids (because these compete at the blood-brain barrier). In conclusion, the effect of TD on mood in formerly de-pressed patients may be more consistent than suggested by these negative findings. A reanalysis of large datasets may determine the relative contribution of extent of deple-tion, medication status, presence of suicidal ideadeple-tion, and time since remission.
A. J. Willem Van der Does, PhD
Departments of Psychology and Psychiatry Leiden University
Wassenaarseweg 52
2333 AK Leiden, the Netherlands
1. Delgado PL, Charney DS, Price LH, Aghajanian G, Landis Heninger GR. Se-rotonin function and the mechanism of antidepressant action. Arch Gen Psy-chiatry. 1990;47:411-418.
2. Smith KA, Fairburn CG, Cowen PJ. Relapse of depression after rapid deple-tion of tryptophan. Lancet. 1997;349:915-919.
3. Moore P, Gillin C, Bhatti T, DeModena A, Seifritz E, Clark C, Stahl S, Rapa-port M, Kelsoe J. Rapid tryptophan depletion, sleep electroencephalogram, and mood in men with remitted depression on serotonin inhibitors. Arch Gen Psychiatry. 1998;55:534-539.
4. Aberg-Wistedt A, Hasselmark L, Stain-Malmgren R, Aperia B, Kjellman BF, Mathe AA. Serotonergic vulnerability in affective disorder. Acta Psychiatr Scand. 1998;97:374-380.
5. Bremner JD, Innis RB, Salomon RM, Staib LH, Ng CK, Miller HL, Bronen RA, Krystal JH, Duncan J, Rich D, Price LH, Malison R, Dey H, Soufer R, Charney DS. Positron emission tomography measurement of cerebral metabolic
cor-relates of tryptophan depletion-induced depressive relapse. Arch Gen Psychia-try. 1997;54:364-374.
6. Leyton M, Young SN, Benkelfat C. Relapse of depression after rapid deple-tion of tryptophan [letter]. Lancet. 1997;349:1840-1841.
7. Spillman MK, Van der Does AJW, Rankin MA, et al. Tryptophan depletion in SSRI-recovered depressed outpatients. Psychopharmacology. In press.
In reply
Like many investigators, we have wondered why some but not all euthymic depressed patients treated with SSRIs or monoamine oxidase inhibitors (MAOIs) suffer a clinical re-lapse following rapid tryptophan depletion (RTD). Many clinical and behavioral measures vary widely between psy-chiatric patients and healthy volunteers with RTD, al-though plasma tryptophan reductions tend to be consistent and robust in both groups. Numerous attempts to correlate changes in plasma tryptophan scores with changes in de-pression scores or other measures have often failed to indi-cate a significant relationship.1-10
Dr Van der Does points out our lack of mood findings and smaller plasma tryptophan depletions compared with other reports.2,11These findings may be attributable to our
depleting tryptophan in the afternoon and evening hours, when plasma tryptophan levels tend to peak,12and this may
have had a blunting effect on plasma tryptophan depletion. However, even with these comparatively smaller deple-tions, each of the 10 remitted depressed patients treated with SSRIs showed significant effects on REM (rapid eye move-ment) sleep measures following both strengths (25 g and 100 g) of a tryptophan-depleting mixture. Therefore, although RTD did not induce depressive relapse in our patients, it did have measurable central nervous system effects consistent with depletion of serotonin. Similarly, in MAOI-treated de-pressed patients, RTD reversed the MAOI-induced suppres-sion of REM sleep without depressive relapse.13Euthymic
patients receiving SSRIs or MAOIs are more vulnerable to RTD-induced relapse early in treatment when they are in partial remission (Hamilton Rating Scale for Depression score, approximately 8-10 at 4-6 weeks) than later in treat-ment when they are in full remission (Hamilton Rating Scale for Depression score, approximately 3 at around 5 months). How should depressive relapse be defined? According to the criteria of Delgado et al,10a 50% increase in
Hamil-ton Rating Scale for Depression score constitutes relapse. Our remitted patients, for example, increased from 2 points to 3 (a 50% increase) on a modified Hamilton Rating Scale for Depression following RTD, but does this truly reflect clini-cal relapse? In our studies of depressed patients and nor-mal volunteers, RTD elicited changes such as increased Con-fusion and decreased Vigor, Elation, and Friendliness in Profile of Mood States subscales. Whether the gap between these changes and depressive relapse is simply a matter of degree remains to be seen. Based on the literature and our own experience, we believe that true depressive relapse in-duced by RTD in SSRI and MAOI euthymia needs to be veri-fied by other groups.
In contrast to our REM sleep findings in SSRI and MAOI-treated depressed patients, the RTD-induced REM sleep effects are less consistent in healthy volunteers,1,2,14
de-spite consistent depletion of plasma tryptophan. In our re-examination of the data, the RTD-induced REM sleep mea-sures in healthy volunteers show an almost dichotomous
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effect: either a very pronounced REM-disinhibiting effect (such as an occurrence of sleep-onset REM) or virtually no effect. In this regard, we agree with Dr Van der Does regarding the notion of a “threshold” effect with RTD, but posit that it is not based in plasma, but located more centrally, such as in neuronal pools of serotonin.
P. J. Moore, PhD J. C. Gillin, MD H. P. Landolt, PhD Mark Rapaport, MD John Kelsoe, MD Department of Psychiatry
University of California at San Diego (UCSD) UCSD Mental Health Clinical Research Center VA San Diego Healthcare System
3350 La Jolla Village Dr San Diego, CA 92161
This study was supported by grant MOI RR00827 from the UCSD General Clinical Research Center, San Diego, Calif, grants MH 57134-01 and MH 18825 from the National In-stitutes of Health, Bethesda, Md; grant MH 30914 from the UCSD Mental Health Clinical Research Center, San Diego, Calif; and the Stanley Foundation, Bethesda, Md.
1. Bhatti T, Gillin JC, Seifritz E, Moore P, Clark C, Golshan S, Stahl S, Rapa-port M, Kelsoe J. Effects of a tryptophan-free amino acid drink challenge on normal human sleep EEG and mood. Biol Psychiatry. 1998;43:52-59. 2. Moore P, Gillin JC, Bhatti T, DeModena A, Seifritz E, Clark C, Stahl S,
Ra-paport M, Kelsoe J. Rapid tryptophan depletion, sleep electroencephalo-gram, and mood in men with remitted depression on serotonin inhibitors. Arch Gen Psychiatry. 1998;55:534-539.
3. Bremner JD, Innis RB, Salomon RM, Staib LH, Ng CK, Miller HL, Bronen RA, Krystal JH, Duncan J, Rich D, Price LH, Malison R, Dey H, Soufer R, Charney DS. Positron emission tomography correlates of tryptophan deple-tion induced depressive relapse. Arch Gen Psychiary. 1997;54:364-374. 4. Neumeister A, Praschak-Rieder N, Hesselman B, Rao M-L, Gluck J, Kasper
S. Effects of tryptophan depletion on drug-free patients with seasonal affec-tive disorder during a stable response to bright light therapy. Arch Gen Psy-chiatry. 1997;54:133-138.
5. Neumeister A, Praschak-Rieder N, Hesselman B, Vitouch O, Rauh, M, Baro-cha A, Kasper S. Effects of tryptophan depletion in fully remitted patients with seasonal affective disorder during summer. Psychological Med 1998;28: 257-264.
6. Lam RW, Zis AP, Grewal A, Delgado PL, Charney DS, Krystal JH. Effects of rapid tryptophan depletion in patients with seasonal affective disorder in re-mission after light therapy. Arch Gen Psychiatry. 1996;53:41-44. 7. Koszycki D, Zacharcko RM, Le Melledo J-M, Young SN, Bradwejn J. Effects
of acute tryptophan depletion on behavioral, cardiovascular and hormonal sensitivity to cholecystokinin-tetrapeptide challenge in healthy volunteers. Biol Psychiatry. 1996;40:648-55.
8. Goddard AW, Charney DS, Germine M, Woods SW, Heninger GR, Krystal JH, Goodman WK, Price LH. Effects of tryptophan depletion on responses to yohimbine in healthy human subjects. Biol Psychiatry. 1996;38:74-85. 9. Ellenbogen MA, Young SN, Dean P, Palmour RM, Benkelfat C. Mood
re-sponse to acute tryptophan depletion in healthy volunteers: sex differences and temporal stability. Neuropsychopharmacology. 1996;15:465-474. 10. Moore P, Landholt HP, Seifritz E, Clark C, Bhatti T, Kelsoe J, Rapaport M,
Gillin JC. Clinical and physiological consequences of rapid tryptophan deple-tion. Neuropsychopharmacology. In press.
11. Delgado PL, Charney DS, Price LH, Aghajanian G, Landis H, Heninger GR. Serotonin function and the mechanism of antidepressant action. Arch Gen Psychiatry. 1990;47:411-418.
12. Wurtman RJ, Rose CM, Chou C, Latin FF. Daily rhythms in the concentra-tions of various amino acids in human plasma. N Engl J Med. 1968;279:171-175.
13. Landolt HP, Schnierow BJ, Kelsoe JR, Rapaport MH, Gillen JC. Phenelzine-induced suppression of REM sleep can be reversed by rapid tryptophan deple-tion. Sleep. 2000;23(suppl 2):A34-A35.
14. Voderholzer U, Hornyak M, Thiel B, Huwig-Poppe C, Kiemen A, Konig A, Backhaus J, Berger M, Hohagen F. Impact of experimentally induced sero-tonin deficiency by tryptophan depletion on sleep EEG in healthy subjects. Neuropsychopharmacology. 1998;18:112-124.
Did Samson Have Antisocial Personality Disorder?
B
esides intrinsic, historical, and literary interest, and pedagogical utility, the study of the history of a disease can provide clues to its pathogen-esis. It is necessary, but not sufficient, that the cause of disease be at least as old as the disease itself. We note a possible case of antisocial personality disorder (ASPD) nearly 3000 years ago: the biblical figure Samson (Judges,1chapters 13-16), son of Manoah.
The DSM-IV requires that 3 of 7 criteria be met for the diagnosis of ASPD. Samson meets 6. (1) Failure to conform to social norms with respect to lawful behav-ior: The Philistines tried to arrest Samson after he burned the Philistine fields (15:5) and went to Gaza (16:1). (2) Deceitfulness, as indicated by repeated lying: Samson did not tell his parents that he had killed a lion. Furthermore, he proffered honey for his parents to eat, but did not tell them it had come from the carcass of a lion (14:9) and thus caused them to violate their dietary laws. (3) Impulsivity: His burning of the Philistine fields (15:5). (4) Irritability and aggressiveness: This is indicated by his repeated involvement in physical fights. (5) Reckless disregard for safety of self or oth-ers: Samson is reported to have taken on and killed 1000 Philistines single-handedly (15:15). Telling Delilah the secret to his strength (16:17), even after she had attempted 3 times previously to get this secret, can also be considered reckless disregard for safety of self. (6) Lack of remorse: He gloated (15:16) after kill-ing 1000 men.
In addition, Samson committed many of the ac-tions listed in the criteria for conduct disorder—fire set-ting, cruelty to small animals (15:5), bullying, initiating physical fights, using a weapon (jawbone of ass) (15: 15), and stealing from a victim (14:19). If conduct dis-order did not start when Samson was younger than 15 years, he was quite young (14:1-6).
Samson shows no evidence of schizophrenia. Some of his behaviors (eg, not telling his parents that the honey had been taken from a carcass) seem to have been done during a nonmanic state.
Samson’s conduct was unacceptable in his time— 3000 Israelites (Samson’s own people!) captured Sam-son and delivered him to the Philistines (15:12).
Recognition of the diagnosis of ASPD for Samson may help in better understanding the biblical story, and, in general, may help in instances when a leader has ASPD. Also, we hope it stimulates interest in the history of ASPD.
Eric Lewin Altschuler, MD, PhD Ansar Haroun, MD
Bing Ho, MD Amy Weimer, MD School of Medicine and
Institute for Neural Computation University of California, San Diego 9500 Gilman Dr, 0109
La Jolla, CA 92093-0109
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